tbuckley/cabot-search huggingface dataset:
High Sensitivity of Shotgun Metagenomic Sequencing in Colon Tissue Biopsy by Host DNA Depletion
Authors: Wing Yin Cheng, Wei-Xin Liu, Yanqiang Ding, Guoping Wang, Yu Shi, Eagle S.H. Chu, Sunny Wong, Joseph J.Y. Sung, Jun Yu
Journal: Genomics Proteomics & Bioinformatics (2022)

Abstract The high host genetic background of tissue biopsies hinders the application of shotgun metagenomic sequencing in characterizing the tissue microbiota. We proposed an optimized method that removed host DNA from colon biopsies and examined the effect on metagenomic analysis. Human or mouse colon biopsies were divided into two groups, with one group undergoing host DNA depletion and the other serving as the control. Host DNA was removed through differential lysis of mammalian and bacterial cells before sequencing. The impact of host DNA depletion on microbiota was compared based on phylogenetic diversity analyses and regression analyses. Removing host DNA enhanced bacterial sequencing depth and improved species discovery, increasing bacterial reads by 2.46 ± 0.20 folds while reducing host reads by 6.80% ± 1.06%. Moreover, 2.40 times more of bacterial species were detected after host DNA depletion. This was confirmed from mouse colon tissues, increasing bacterial reads by 5.46 ± 0.42 folds while decreasing host reads by 10.2% ± 0.83%. Similarly, significantly more bacterial species were detected in the mouse colon tissue upon host DNA depletion (P &amp;lt; 0.001). Furthermore, an increased microbial richness was evident in the host DNA-depleted samples compared with non-depleted controls in human colon biopsies and mouse colon tissues (P &amp;lt; 0.001). Our optimized method of host DNA depletion improves the sensitivity of shotgun metagenomic sequencing in bacteria detection in the biopsy, which may yield a more accurate taxonomic profile of the tissue microbiota and identify bacteria that are important for disease initiation or progression.
Longitudinal characterization of circulating neutrophils uncovers phenotypes associated with severity in hospitalized COVID-19 patients
Authors: Thomas J. LaSalle, Anna L.K. Gonye, Samuel S. Freeman, Paulina Kaplonek, Irena Gushterova, Kyle R. Kays, Kasidet Manakongtreecheep, Jessica Tantivit, Maricarmen Rojas-Lopez, Brian C. Russo, Nihaarika Sharma, Molly F. Thomas, Kendall M. Lavin-Parsons, Brendan M. Lilly, Brenna N. Mckaig, Nicole C. Charland, Hargun K. Khanna, Carl L. Lodenstein, Justin D. Margolin, Emily M. Blaum, Paola B. Lirofonis, Or-Yam Revach, Arnav Mehta, Abraham Sonny, Roby P. Bhattacharyya, Blair Alden Parry, Marcia B. Goldberg, Galit Alter, Michael R. Filbin, Alexandra-Chloé Villani, Nir Hacohen, Moshe Sade-Feldman
Journal: Cell Reports Medicine (2022)

Mechanisms of neutrophil involvement in severe coronavirus disease 2019 (COVID-19) remain incompletely understood. Here, we collect longitudinal blood samples from 306 hospitalized COVID-19+ patients and 86 controls and perform bulk RNA sequencing of enriched neutrophils, plasma proteomics, and high-throughput antibody profiling to investigate relationships between neutrophil states and disease severity. We identify dynamic switches between six distinct neutrophil subtypes. At days 3 and 7 post-hospitalization, patients with severe disease display a granulocytic myeloid-derived suppressor cell-like gene expression signature, while patients with resolving disease show a neutrophil progenitor-like signature. Humoral responses are identified as potential drivers of neutrophil effector functions, with elevated severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific immunoglobulin G1 (IgG1)-to-IgA1 ratios in plasma of severe patients who survived. In vitro experiments confirm that while patient-derived IgG antibodies induce phagocytosis in healthy donor neutrophils, IgA antibodies predominantly induce neutrophil cell death. Overall, our study demonstrates a dysregulated myelopoietic response in severe COVID-19 and a potential role for IgA-dominant responses contributing to mortality.
NAFLD and thyroid function: pathophysiological and therapeutic considerations
Authors: Erifili Hatziagelaki, Stavroula A Paschou, Martin Schön, Theodora Psaltopoulou, Michael Roden
Journal: Trends in Endocrinology and Metabolism (2022)

Nonalcoholic fatty liver disease (NAFLD) is a worldwide rising challenge because of hepatic, but also extrahepatic, complications. Thyroid hormones are master regulators of energy and lipid homeostasis, and the presence of abnormal thyroid function in NAFLD suggests pathogenic relationships. Specifically, persons with hypothyroidism feature dyslipidemia and lower hepatic β-oxidation, which favors accumulation of triglycerides and lipotoxins, insulin resistance, and subsequently de novo lipogenesis. Recent studies indicate that liver-specific thyroid hormone receptor β agonists are effective for the treatment of NAFLD, likely due to improved lipid homeostasis and mitochondrial respiration, which, in turn, may contribute to a reduced risk of NAFLD progression. Taken together, the possible coexistence of thyroid disease and NAFLD calls for increased awareness and optimized strategies for mutual screening and management.
Predicting dupilumab treatment outcome in patients with primary diffuse type 2 chronic rhinosinusitis
Authors: Michael B. Soyka, Fabio S. Ryser, Catrin Brühlmann, Danielle Fehr, Jacqueline Dülgeroglu, Peter Schmid‐Grendelmeier, Marie‐Charlotte Brüggen, Urs C. Steiner
Journal: Allergy (2022)

Chronic rhinosinusitis with a type 2 inflammatory pattern (T2CRS) is believed to be restricted to the nose and sinuses and associated with polyps, without clear serologic markers. Dupilumab is a promising new therapy in difficult to treat T2CRS. No factors are known to predict dupilumab treatment outcome.Patients undergoing dupilumab treatment were assessed clinically to report ultra-short- and short-term outcome up to 90 days. Serum samples were taken on day 0 and 30 days of treatment, and proteomic analyses were performed using Olink®. The results were compared with healthy controls (HC). The aim was to identify clinical and serological markers associated with a treatment response to dupilumab. Confirmation of predictive parameters was evaluated in a prospective cohort of 20 T2CRS patients.Thirty patients were included, 80% of which were treatment responders. SinoNasalOutcomeTest-20 (SNOT-20) scores and the total nasal polyp score improved significantly (p < .05) on Day 7. An improvement of 2.5 points at the first visit was associated with a favorable outcome with a sensitivity of 86%. Proteomic analyses revealed significant changes compared with HC. Furthermore, we could identify OPG in the serum of dupilumab-treated patients that may serve as a predictor of the clinical outcome of dupilumab treatment. The predictive value of OPG was confirmed in the second cohort.Clinical response after 1 week of treatment with dupilumab is highly associated with a favorable outcome. High sensitivity proteomic analyses can identify T2CRS-specific dysregulated proteins in serum. Serum OPG may serve as a predictor for dupilumab treatment outcome before the initiation of any therapy.
Splenic red pulp macrophages provide a niche for CML stem cells and induce therapy resistance
Authors: Elias D. Bührer, Michael A. Amrein, Stefan Forster, Stephan Isringhausen, Christian M. Schürch, Salil S. Bhate, Tess Brodie, Joel Zindel, Deborah Stroka, Mohamad Al Sayed, César Nombela-Arrieta, Ramin Radpour, Carsten Riether, Adrian F. Ochsenbein
Journal: Leukemia (2022)

Abstract Disease progression and relapse of chronic myeloid leukemia (CML) are caused by therapy resistant leukemia stem cells (LSCs), and cure relies on their eradication. The microenvironment in the bone marrow (BM) is known to contribute to LSC maintenance and resistance. Although leukemic infiltration of the spleen is a hallmark of CML, it is unknown whether spleen cells form a niche that maintains LSCs. Here, we demonstrate that LSCs preferentially accumulate in the spleen and contribute to disease progression. Spleen LSCs were located in the red pulp close to red pulp macrophages (RPM) in CML patients and in a murine CML model. Pharmacologic and genetic depletion of RPM reduced LSCs and decreased their cell cycling activity in the spleen. Gene expression analysis revealed enriched stemness and decreased myeloid lineage differentiation in spleen leukemic stem and progenitor cells (LSPCs). These results demonstrate that splenic RPM form a niche that maintains CML LSCs in a quiescent state, resulting in disease progression and resistance to therapy.
Myeloid-derived suppressor cells: an emerging target for anticancer immunotherapy
Authors: Yuze Wu, Ming Yi, Mengke Niu, Qi Mei, Kongming Wu
Journal: Molecular Cancer (2022)

Abstract The clinical responses observed following treatment with immune checkpoint inhibitors (ICIs) support immunotherapy as a potential anticancer treatment. However, a large proportion of patients cannot benefit from it due to resistance or relapse, which is most likely attributable to the multiple immunosuppressive cells in the tumor microenvironment (TME). Myeloid-derived suppressor cells (MDSCs), a heterogeneous array of pathologically activated immature cells, are a chief component of immunosuppressive networks. These cells potently suppress T-cell activity and thus contribute to the immune escape of malignant tumors. New findings indicate that targeting MDSCs might be an alternative and promising target for immunotherapy, reshaping the immunosuppressive microenvironment and enhancing the efficacy of cancer immunotherapy. In this review, we focus primarily on the classification and inhibitory function of MDSCs and the crosstalk between MDSCs and other myeloid cells. We also briefly summarize the latest approaches to therapies targeting MDSCs.
Coemergence of the Amphipathic Helix on Ameloblastin With Mammalian Prismatic Enamel
Authors: Jingtan Su, Rucha Arun Bapat, Gayathri Visakan, Janet Moradian-Oldak
Journal: Molecular Biology and Evolution (2022)

Abstract To investigate correlation between the ameloblastin (Ambn) amino acid sequence and the emergence of prismatic enamel, a notable event in the evolution of ectodermal hard tissues, we analyzed Ambn sequences of 53 species for which enamel microstructures have been previously reported. We found that a potential amphipathic helix (AH) within the sequence encoded by Exon 5 of Ambn appeared in species with prismatic enamel, with a few exceptions. We studied this correlation by investigating synthetic peptides from different species. A blue shift in fluorescence spectroscopy suggested that the peptides derived from mammalian Ambn interacted with liposomes. A downward shift at 222 nm in circular dichroism spectroscopy of the peptides in the presence of liposomes suggested that the peptides of mammals with prismatic enamel underwent a transition from disordered to helical structure. The peptides of species without prismatic enamel did not show similar secondary structural changes in the presence of liposomes. Peptides of mammals with prismatic enamel caused liposome leakage and inhibited LS8 and ALC cell spreading regulated by full-length Ambn. RT-PCR showed that AH is involved in Ambn’s regulation of cell polarization genes: Vangl2, Vangl1, Prickle1, ROCK1, ROCK2, and Par3. Our comprehensive sequence analysis clearly demonstrates that AH motif is closely related to the emergence of enamel prismatic structure, providing insight into the evolution of complex enamel microstructure. We speculate that the AH motif evolved in mammals to interact with cell membrane, triggering signaling pathways required for specific changes in cell morphology associated with the formation of enamel prismatic structure.
Romiplostim use in pregnant women with immune thrombocytopenia
Authors: James B. Bussel, Nichola Cooper, Tatiana Lawrence, Marc Michel, Emilie Vander Haar, Kejia Wang, Hongmei Wang, Hossam Saad
Journal: American Journal of Hematology (2022)

Abstract Treatment for immune thrombocytopenia (ITP) in pregnancy is hampered by the lack of fetal safety evidence of maternally‐administered medications. The Pregnancy Surveillance Program (PSP) collected patient information from 2017–2020 for pregnancy, birth outcomes, and adverse events (AEs) for 186 women exposed to romiplostim from 20 days before pregnancy to the end of pregnancy. Timing of exposure was available in 128 women. Seventy‐one mothers (38%) had prepregnancy exposure to romiplostim; intrapartum exposure was known for the first (for many mothers when they discovered their pregnancy), second, and third trimesters for 74 (40%), 22 (12%), and 44 (24%) mothers, respectively, with 15 mothers exposed during &gt;1 trimester. Among the 86 mothers with known pregnancy outcomes, 46 (53%) had at least one pregnancy‐related serious AE (SAE); approximately 2/3 of SAEs were due to underlying ITP. Of 92 mothers with known birth outcomes, 60 (65%) had a normal pregnancy and 16 (17%) had complications, with both categories including term and preterm births; there were 12 (14%) spontaneous miscarriages/stillbirths, 3 (3%) ectopic pregnancies, and 1 (1%) molar pregnancy. Most abnormal births resulted from abnormal pregnancies. There were five neonatal/postnatal AEs of note: inguinal hernia, cytomegalovirus infection, trisomy 8 (third trimester single‐dose romiplostim exposure), single umbilical artery without known anomalies, and development of autism at age 2 years. Seven of 12 infants with neonatal thrombocytopenia had resolution of thrombocytopenia before discharge; all 12 were discharged. Review of pregnancies in women exposed to romiplostim did not reveal any specific safety concerns for mothers, fetuses, or infants.
Dynamic Changes in the NK-, Neutrophil-, and B-cell Immunophenotypes Relevant in High Metastatic Risk Post Neoadjuvant Chemotherapy–Resistant Early Breast Cancers
Authors: Patrycja Gazinska, Charlotte Milton, Jacopo Iacovacci, Joseph Ward, Richard Buus, Thanussuyah Alaguthurai, Rosalind Graham, Ayse Akarca, Esther Lips, Kalnisha Naidoo, Jelle Wesseling, Teresa Marafioti, Maggie Cheang, Cheryl Gillett, Yin Wu, Aadil Khan, Alan Melcher, Roberto Salgado, Mitch Dowsett, Andrew Tutt, Ioannis Roxanis, Syed Haider, Sheeba Irshad
Journal: Clinical Cancer Research (2022)

To identify potential immune targets in post-neoadjuvant chemotherapy (NAC)-resistant triple-negative breast cancer (TNBC) and ER+HER2- breast cancer disease.
Differences in healthy longevity by HIV status and viral load among older South African adults: an observational cohort modelling study
Authors: Collin F Payne, Brian Houle, Chido Chinogurei, Carlos Riumallo Herl, Chodziwadziwa Whiteson Kabudula, Lindsay C Kobayashi, Joshua A Salomon, Jennifer Manne-Goehler
Journal: The Lancet HIV (2022)
Trends and risk of lung cancer among people living with HIV in the USA: a population-based registry linkage study
Authors: Cameron B Haas, Eric A Engels, Marie-Josèphe Horner, Neal D Freedman, Qianlai Luo, Susan Gershman, Baozhen Qiao, Ruth M Pfeiffer, Meredith S Shiels
Journal: The Lancet HIV (2022)
Effect of a conditional cash transfer programme on AIDS incidence, hospitalisations, and mortality in Brazil: a longitudinal ecological study
Authors: Gabriel Alves de Sampaio Morais, Laio Magno, Andrea F Silva, Nathalia S Guimarães, José Alejandro Ordoñez, Luís Eugênio Souza, James Macinko, Inês Dourado, Davide Rasella
Journal: The Lancet HIV (2022)
Artificial intelligence-guided screening for atrial fibrillation using electrocardiogram during sinus rhythm: a prospective non-randomised interventional trial
Authors: Peter A Noseworthy, Zachi I Attia, Emma M Behnken, Rachel E Giblon, Katherine A Bews, Sijia Liu, Tara A Gosse, Zachery D Linn, Yihong Deng, Jun Yin, Bernard J Gersh, Jonathan Graff-Radford, Alejandro A Rabinstein, Konstantinos C Siontis, Paul A Friedman, Xiaoxi Yao
Journal: The Lancet (2022)
Further humoral immunity evasion of emerging SARS-CoV-2 BA.4 and BA.5 subvariants
Authors: Fanchong Jian, Yuanling Yu, Weiliang Song, Ayijiang Yisimayi, Lingling Yu, Yuxue Gao, Na Zhang, Yao Wang, Fei Shao, Xiaohua Hao, Yanli Xu, Ronghua Jin, Youchun Wang, Xiaoliang Sunney Xie, Yunlong Cao
Journal: The Lancet Infectious Diseases (2022)
Diagnosis and classification of optic neuritis
Authors: Axel Petzold, Clare L Fraser, Mathias Abegg, Raed Alroughani, Daniah Alshowaeir, Regina Alvarenga, Cécile Andris, Nasrin Asgari, Yael Barnett, Roberto Battistella, Raed Behbehani, Thomas Berger, Mukharram M Bikbov, Damien Biotti, Valerie Biousse, Antonella Boschi, Milan Brazdil, Andrei Brezhnev, Peter A Calabresi, Monique Cordonnier, Fiona Costello, Franz M Cruz, Leonardo Provetti Cunha, Smail Daoudi, Romain Deschamps, Jerome de Seze, Ricarda Diem, Masoud Etemadifar, Jose Flores-Rivera, Pedro Fonseca, Jette Frederiksen, Elliot Frohman, Teresa Frohman, Caroline Froment Tilikete, Kazuo Fujihara, Alberto Gálvez, Riadh Gouider, Fernando Gracia, Nikolaos Grigoriadis, José M Guajardo, Mario Habek, Marko Hawlina, Elena H Martínez-Lapiscina, Juzar Hooker, Jyh Yung Hor, William Howlett, Yumin Huang-Link, Zhannat Idrissova, Zsolt Illes, Jasna Jancic, Panitha Jindahra, Dimitrios Karussis, Emilia Kerty, Ho Jin Kim, Wolf Lagrèze, Letizia Leocani, Netta Levin, Petra Liskova, Yaou Liu, Youssoufa Maiga, Romain Marignier, Chris McGuigan, Dália Meira, Harold Merle, Mário L R Monteiro, Anand Moodley, Frederico Moura, Silvia Muñoz, Sharik Mustafa, Ichiro Nakashima, Susana Noval, Carlos Oehninger, Olufunmilola Ogun, Afekhide Omoti, Lekha Pandit, Friedemann Paul, Gema Rebolleda, Stephen Reddel, Konrad Rejdak, Robert Rejdak, Alfonso J Rodriguez-Morales, Marie-Bénédicte Rougier, Maria Jose Sa, Bernardo Sanchez-Dalmau, Deanna Saylor, Ismail Shatriah, Aksel Siva, Hadas Stiebel-Kalish, Gabriella Szatmary, Linh Ta, Silvia Tenembaum, Huy Tran, Yevgen Trufanov, Vincent van Pesch, An-Guor Wang, Mike P Wattjes, Ernest Willoughby, Magd Zakaria, Jasmin Zvornicanin, Laura Balcer, Gordon T Plant
Journal: The Lancet Neurology (2022)
Safety and efficacy of oral fexinidazole in children with gambiense human African trypanosomiasis: a multicentre, single-arm, open-label, phase 2–3 trial
Authors: Victor Kande Betu Kumesu, Wilfried Mutombo Kalonji, Clélia Bardonneau, Olaf Valverde Mordt, Digas Ngolo Tete, Séverine Blesson, François Simon, Sophie Delhomme, Sonja Bernhard, Pathou Nganzobo Ngima, Hélène Mahenzi Mbembo, Jean-Pierre Fina Lubaki, Steven Lumeya Vuvu, Willy Kuziena Mindele, Médard Ilunga Wa Kyhi, Guylain Mandula Mokenge, Lewis Kaninda Badibabi, Augustin Kasongo Bonama, Papy Kavunga Lukula, Crispin Lumbala, Bruno Scherrer, Nathalie Strub-Wourgaft, Antoine Tarral
Journal: The Lancet Global Health (2022)
A <i>CLAVATA3</i>-like Gene Acts as a Gynoecium Suppression Function in White Campion
Authors: Yusuke Kazama, Moe Kitoh, Taiki Kobayashi, Kotaro Ishii, Marc Krasovec, Yasuo Yasui, Tomoko Abe, Shigeyuki Kawano, Dmitry A Filatov
Journal: Molecular Biology and Evolution (2022)

Abstract How do separate sexes originate and evolve? Plants provide many opportunities to address this question as they have diverse mating systems and separate sexes (dioecy) that evolved many times independently. The classic “two-factor” model for evolution of separate sexes proposes that males and females can evolve from hermaphrodites via the spread of male and female sterility mutations that turn hermaphrodites into females and males, respectively. This widely accepted model was inspired by early genetic work in dioecious white campion (Silene latifolia) that revealed the presence of two sex-determining factors on the Y-chromosome, though the actual genes remained unknown. Here, we report identification and functional analysis of the putative sex-determining gene in S. latifolia, corresponding to the gynoecium suppression factor (GSF). We demonstrate that GSF likely corresponds to a Y-linked CLV3-like gene that is specifically expressed in early male flower buds and encodes the protein that suppresses gynoecium development in S. latifolia. Interestingly, GSFY has a dysfunctional X-linked homolog (GSFX) and their synonymous divergence (dS = 17.9%) is consistent with the age of sex chromosomes in this species. We propose that female development in S. latifolia is controlled via the WUSCHEL-CLAVATA feedback loop, with the X-linked WUSCHEL-like and Y-linked CLV3-like genes, respectively. Evolution of dioecy in the S. latifolia ancestor likely involved inclusion of ancestral GSFY into the nonrecombining region on the nascent Y-chromosome and GSFX loss of function, which resulted in disbalance of the WUSCHEL-CLAVATA feedback loop between the sexes and ensured gynoecium suppression in males.
The <i>cnf1</i> gene is associated with an expanding <i>Escherichia coli</i> ST131 <i>H</i> 30Rx/C2 subclade and confers a competitive advantage for gut colonization
Authors: Landry L. Tsoumtsa Meda, Luce Landraud, Serena Petracchini, Stéphane Descorps-Declere, Emeline Perthame, Marie-Anne Nahori, Laura Ramirez Finn, Molly A. Ingersoll, Rafael Patiño-Navarrete, Philippe Glaser, Richard Bonnet, Olivier Dussurget, Erick Denamur, Amel Mettouchi, Emmanuel Lemichez
Journal: Gut Microbes (2022)

Epidemiological projections point to acquisition of ever-expanding multidrug resistance (MDR) by
Lovo‐cel gene therapy for sickle cell disease: Treatment process evolution and outcomes in the initial groups of the <scp>HGB</scp>‐206 study
Authors: Julie Kanter, Alexis A. Thompson, Francis J. Pierciey, Matthew Hsieh, Naoya Uchida, Philippe Leboulch, Manfred Schmidt, Melissa Bonner, Ruiting Guo, Alex Miller, Jean‐Antoine Ribeil, David Davidson, Mohammed Asmal, Mark C. Walters, John F. Tisdale
Journal: American Journal of Hematology (2022)

Abstract lovo‐cel (bb1111; LentiGlobin for sickle cell disease [SCD]) gene therapy (GT) comprises autologous transplantation of hematopoietic stem and progenitor cells transduced with the BB305 lentiviral vector encoding a modified β‐globin gene (β A‐T87Q ) to produce anti‐sickling hemoglobin (HbA T87Q ). The efficacy and safety of lovo‐cel for SCD are being evaluated in the ongoing phase 1/2 HGB‐206 study ( ClinicalTrials.gov : NCT02140554). The treatment process evolved over time, using learnings from outcomes in the initial patients to optimize lovo‐cel's benefit–risk profile. Following modest expression of HbA T87Q in the initial patients (Group A, n = 7), alterations were made to the treatment process for patients subsequently enrolled in Group B ( n = 2, patients B1 and B2), including improvements to cell collection and lovo‐cel manufacturing. After 6 months, median Group A peripheral blood vector copy number (≥0.08 c/dg) and HbA T87Q levels (≥0.46 g/dL) were inadequate for substantial clinical effect but stable and sustained over 5.5 years; both markedly improved in Group B (patient B1: ≥0.53 c/dg and ≥2.69 g/dL; patient B2: ≥2.14 c/dg and ≥6.40 g/dL, respectively) and generated improved biologic and clinical efficacy in Group B, including higher total hemoglobin and decreased hemolysis. The safety of the lovo‐cel for SCD treatment regimen largely reflected the known side effects of HSPC collection, busulfan conditioning regimen, and underlying SCD; acute myeloid leukemia was observed in two patients in Group A and deemed unlikely related to insertional oncogenesis. Changes made during development of the lovo‐cel treatment process were associated with improved outcomes and provide lessons for future SCD GT studies.
Single-cell multi-omics profiling links dynamic DNA methylation to cell fate decisions during mouse early organogenesis
Authors: Stephen J. Clark, Ricard Argelaguet, Tim Lohoff, Felix Krueger, Deborah Drage, Berthold Göttgens, John C. Marioni, Jennifer Nichols, Wolf Reik
Journal: Genome biology (2022)

Perturbation of DNA methyltransferases (DNMTs) and of the active DNA demethylation pathway via ten-eleven translocation (TET) methylcytosine dioxygenases results in severe developmental defects and embryonic lethality. Dynamic control of DNA methylation is therefore vital for embryogenesis, yet the underlying mechanisms remain poorly understood.